1. Field of the Invention
The present invention relates generally to methods for smoking cessation assistance, and more particularly to methods for determining and predicting dosages utilized in nicotine replacement therapy employed in conjunction with smoking cessation techniques.
Cigarette smoking is a serious health concern in the United States and throughout the world, being a significant causative factor in several types of cancer, heart disease, and other disabilities. While the risk of these diseases can be greatly reduced by simply stopping smoking, tobacco dependency makes stopping very difficult for many patients. Thus, there is a continuing need to provide aids for use in smoking cessation therapy.
Of particular interest to the present invention, a number of products have been commercially developed for providing nicotine replacement while a patient is undergoing smoking cessation and may suffer the symptoms of nicotine withdrawal. Such nicotine replacement can be achieved by a variety of products, including gums, transdermal patches, nasal spray, inhalers, lozenges, and the like. Frequently, the use of such nicotine replacement products will be combined with physician counseling, group and/or psychological counseling to further increase the chances of long term sustained abstinence.
While a significant improvement over counseling alone, nicotine replacement therapy is not always successful. Nicotine replacement alone (defined as at least one year of sustained abstinence from smoking) achieves a success rate in the range from 0% to 12%, while nicotine replacement combined with counseling achieves a success in the range from 25% to 38%.
It would therefore be desirable to provide improved methods and therapies for assisting in smoking cessation. It would be particularly desirable to provide methods for further increasing the success of nicotine replacement therapy, both by itself and in combination with other smoking cessation, aids. Such methods should be straightforward and preferably require a minimum of patient follow-up. Such methods should also be efficient, adding little to the cost of therapy while achieving significantly higher compliance rates. These and other objectives will be met, in whole and in part, by the invention of the present application as described in more detail hereinbelow.
2. Description of the Background Art
U.S. Pat. No. 5,069,904, describes nicotine therapy for disease treatment where dosage is determined by incrementally increasing the administered amount until a putative therapeutic dosage is achieved. Nicotine patches intended for delivering safe and steady blood plasma levels of nicotine are described in various patent publications, including U.S. Pat. No. 4,943,435. The pharmacokinetics of nicotine patch replacement is described in various journal publications, including Fiore et al. (1992) J. Am. Med. Assn. 268:2687-2694; Ross et al. (1991) Pharm. Res. 8:385-388; Chan et al. (1990) J. Controlled Release 14:145-151; Kochak et al. (1992) Pharm. Res. 9:1451-1455; and Minneker et al. (1989) Meth. Find. Exp. Clin. Pharmacol. 11:219-222. The Minneker et al. (1989) publication reported that nicotine transdermal replacement dosages adapted to previous daily cigarette consumption was no more effective than a standard dosage for achieving successful smoking cessation therapy.
The present invention is based on the observation that patient success in smoking cessation therapy correlates strongly with the degree to which the nicotine replacement therapy is able to be achieved in relation to pre-cessation blood levels of nicotine. In particular, it is observed herein that long term patient abstinence is achieved more often in those patients where at least about 40%, usually at least about 50%, of pre-cessation blood nicotine levels (measured as a nicotine metabolite, usually cotinine) are maintained by the replacement therapy. Surprisingly, however, it is also observed herein that nicotine replacement levels of blood cannot be adequately predicted based upon the level of administered dosage alone. That is, blood nicotine levels appear to depend on a number of individual patient factors in addition to the replacement dosage.
Thus, the present invention provides methods for determining nicotine replacement dosages for effective smoking cessation in patients, where an initial nicotine replacement dosage is determined based on a number of patient characteristics selected from the group consisting of a body mass factor, a cumulative smoking factor, a psychological dependence factor, age, and menopausal status. Such dosages are selected to achieve replacement nicotine concentrations in blood meeting a desired threshold amount, typically at least about 50% of the pre-cessation nicotine levels.
The preferred patient characteristics will vary between males and females. For males, the preferred patient characteristics include at least the body mass factor and the cumulative smoking factor. The psychological dependence factor and patient age are also useful, although not as predictive as the body mass factor and cumulative smoking factor. For females, the preferred patient characteristics include at least the psychological dependence factor and age. Menopausal status is also a significant factor, with the body mass factor also being significant, although less so than the previously mentioned factors. The cumulative smoking factor appears to be of little relevance to predicting the relationship between dosage and blood nicotine levels in women.
The present invention also provides a method for determining the relationship between nicotine dosage and nicotine serum levels in a population of patients who smoke tobacco. The method relies on measuring blood nicotine concentrations in individual patients while said patients are smoking. After the patients have stopped smoking, known dosages of nicotine are administered and blood nicotine concentrations measured, while the patient remains abstinent from smoking. At least two values corresponding to the patient characteristics set forth above are determined for each individual patient in the population, and a relationship between the nicotine dosage and nicotine blood concentration as a function of both the blood nicotine concentration while smoking and at least two patient characteristics can then be determined by known mathematical techniques, such as regression analysis.
It is important to reach the target blood nicotine level, delivered by the therapeutic medication, as rapidly as possible after smoking cessation, referred to as the patient""s Target Quit Date. If there is delay, and the blood nicotine level is too low, then risk of relapse back to smoking can increase 10-fold in the first day or two after Target Quit Date. Conversely, if the physician initiates treatment with too high a therapeutic nicotine medication dose, then the patient could experience untoward side effects, such as nausea or vomiting, causing the patient to stop medication and likely relapse back to smoking. The present invention allows the physician to start the patient with the proper dose of nicotine replacement medication which individually optimizes that patient""s chance of successfully stopping smoking.
The initial dosages predicted by the method of the present invention are often counter-intuitive. For example the method provides for substantially higher nicotine patch doses to achieve adequate nicotine replacement blood level in short, obese men (the prototypical, paunchy beer-bellied man), then in men of average body build. While this finding might make common sense, consider what the method predicts for women: The tall, slender womanxe2x80x94the xe2x80x9cidealxe2x80x9d fashion modelxe2x80x94also needs a substantially higher nicotine patch dose to receive adequate treatment than does a woman of average body build. Thus, the short, obese man and the tall, slender woman each need high nicotine patch doses, while the tall, thin man, and the short, obese woman each need low nicotine patch doses to attain the same resulting therapeutic nicotine level in the blood.